title: The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities.
abstract: MicroRNAs (miRNAs) are noncoding small RNAs that repress protein translation by targeting specific messenger RNAs. miR-15a and miR-16-1 act as putative tumor suppressors by targeting the oncogene BCL2. These miRNAs form a cluster at the chromosomal region 13q14, which is frequently deleted in cancer. Here, we report that the miR-15a and miR-16-1 cluster targets CCND1 (encoding cyclin D1) and WNT3A, which promotes several tumorigenic features such as survival, proliferation and invasion. In cancer cells of advanced prostate tumors, the miR-15a and miR-16 level is significantly decreased, whereas the expression of BCL2, CCND1 and WNT3A is inversely upregulated. Delivery of antagomirs specific for miR-15a and miR-16 to normal mouse prostate results in marked hyperplasia, and knockdown of miR-15a and miR-16 promotes survival, proliferation and invasiveness of untransformed prostate cells, which become tumorigenic in immunodeficient NOD-SCID mice. Conversely, reconstitution of miR-15a and miR-16-1 expression results in growth arrest, apoptosis and marked regression of prostate tumor xenografts. Altogether, we propose that miR-15a and miR-16 act as tumor suppressor genes in prostate cancer through the control of cell survival, proliferation and invasion. These findings have therapeutic implications and may be exploited for future treatment of prostate cancer.
authors.forename: Désirée
authors.initials: D
authors.lastname: Bonci
authors.forename: Valeria
authors.initials: V
authors.lastname: Coppola
authors.forename: Maria
authors.initials: M
authors.lastname: Musumeci
authors.forename: Antonio
authors.initials: A
authors.lastname: Addario
authors.forename: Raffaella
authors.initials: R
authors.lastname: Giuffrida
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Memeo
authors.forename: Leonardo
authors.initials: L
authors.lastname: D'Urso
authors.forename: Alfredo
authors.initials: A
authors.lastname: Pagliuca
authors.forename: Mauro
authors.initials: M
authors.lastname: Biffoni
authors.forename: Catherine
authors.initials: C
authors.lastname: Labbaye
authors.forename: Monica
authors.initials: M
authors.lastname: Bartucci
authors.forename: Giovanni
authors.initials: G
authors.lastname: Muto
authors.forename: Cesare
authors.initials: C
authors.lastname: Peschle
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060508:Wnt3 Protein; D060509:Wnt3A Protein
chemical_list: D035683:MicroRNAs; D015513:Oncogene Proteins; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D019938:Cyclin D1